Despite the emergence of an increased number of molecular targeted agents, the prognosis for patients with metastatic colorectal cancer (CRC) remains poor with 5 year survival rates of <10%. Agents targeting epidermal growth factor receptor (EGFR) have met with limited success in the clinical treatment of CRC and are limited to treatment of those patients whose tumors do not harbor mutations in KRAS or BRAF. Approximately 10% of colorectal malignancies are known to possess a BRAF valine 600 (BRAFV???) mutation, conferring an extremely poor prognosis. Reactivation of the MAP kinase pathway by EGFR and the co-occurrence of PIK3A mutations or loss of expression of the tumor suppressor PTEN serve to render BRAFmt tumors refractory to MEK or BRAF inhibitor monotherapies. Our central hypothesis is that a dual small molecule inhibitor that potently and selectively targets only EGFR and PI3KA in combination with an inhibitor of MAP kinase signaling represents a viable strategy for the treatment of BRAF mutant colorectal cancers. To test this hypothesis, we have designed small molecules that exhibit potent and selective dual inhibition of EGFR and PIK3A family members. To the best of our knowledge, the lead compound MTX-211 represents a first in class selective inhibitor of these two critical oncogenic kinases. We have generated crystallographic evidence confirming that MTX-211 binds to these two kinases in the manner predicted from its computational design, adopting a flipped binding mode to selectively and potently inhibit both EGFR and PI3K. Preliminary data have shown a striking increase in lifespan of mice implanted with patient-derived BRAFmt CRC when treated with the combination of MTX-211 and the MEK inhibitor trametinib. We now propose to carry out more extensive preclinical testing of MTX-211 in patient derived xenograft models established from patients diagnosed with BRAFmt CRC to bolster the case for this clinical development path. Molecular profiling will be carried out to elucidate markers that correlate with inherent sensitivity as well as the adaptive signaling changes that lead to progression. Additionally, we propose to maximize durability of response by carrying out comparative efficacy studies of MTX-211 combined with clinically approved MEK versus RAF inhibitors to inform the design of future clinical trials of this promising drug candidate for treatment of this recalcitrant disease.